FAM46C/TENT5C Is a Tumour Suppressor in Gastric Adenocarcinoma

Despite improvements in surgical and perioperative adjuvant therapy, gastric adenocarcinoma carries a 75% case-fatality rate and approximately 40% of Western patients die of recurrent disease. As an important regulator of centriolar duplication, cell motility, and invasion, polo-like kinase 4 (PLK4) has been identified as an oncogene which affects tumourigenesis, cancer metastasis, and response to chemotherapy. Change in PLK4 expression has been identified in numerous human cancers, but Plk4’s role in gastric adenocarcinoma is not well defined; I hypothesized that Plk4 or its interactors could be intimately involved in gastric cancer metastasis and progression. The high degree of molecular heterogeneity in gastric adenocarcinoma and variability in patient outcomes highlight the importance of utilizing patient cohorts to identify novel therapeutic targets. As such, I performed a comprehensive clinical chart review of 238 consecutive gastric adenocarcinoma patients who underwent a curative-intent resection. Recurrence remained a major cause of death in this patient cohort and was only predicted by pathologic staging. Our laboratory had previously identified a number of high-confidence functional interactors of Plk4, and, for each interactor, I determined the mRNA expression in tumour vs paired normal mucosa in our patient cohort. From this interrogation, I identified low expression of FAM46C, a Plk4 inhibitor and tumour suppressor in multiple myeloma, as a novel predictor of inferior disease-specific survival and recurrence at locoregional or distant sites. In vitro experiments demonstrate that FAM46C expression is cytotoxic to gastric cancer cells and suppresses cell migration. RNA-sequencing of patients’ gastric tumour and normal mucosa further reveal that ion-channel related pathways are significantly dysregulated in low-FAM46C tumours, but not in high-FAM46C tumours, implying a novel relationship between FAM46C and ion channels. Targeted evaluation revealed a correlation between the expression of FAM46C and KCNQ1, the main potassium recycler in parietal cells, both in vitro and in patient samples. FAM46C-depleted gastric cancer cells were also better able to survive in a high KCl concentration environment. These findings provide support for FAM46C as a tumour suppressor and therapeutic target in gastric adenocarcinoma patients, and potentially reveal a new role for FAM46C in regulating KCNQ1-mediated evasion of apoptosis and epithelial-to-mesenchymal transition.Ph.D

Predictors of treatment failure for pneumatic retinopexy

Objective: The purpose of this study was to define the overall anatomic success rate in pneumatic retinopexy and to identify morphologic features that may be predictive of treatment failure in pneumatic retinopexy. Design and Participants: Prospective consecutive interventional case series of patients with new-onset primary rhegmatogenous retinal detachments treated with pneumatic retinopexy. Methods: In this interventional case series, consecutive patients with new-onset primary rhegmatogenous retinal detachments were treated with pneumatic retinopexy and followed prospectively. Morphologic data were collected on 3-colour fundus drawings. The primary outcome measure was treatment failure, defined as requirement for scleral buckle or vitrectomy within the follow-up period. Rates of failure for each morphologic feature were compared and a logistic regression model was fit. Results: A total of 113 eyes were included in the study. Anatomic success was achieved in 69.6% of patients. Morphologic criteria including the position and number of breaks, position and extent of lattice degeneration, size of the detached area, and macular status were all found not to be significantly related to failure. In multivariate analysis, only 3 predictors, pseudophakic status (p < 0.05, odds ratio [OR] 2.9, 95% CI, 1.06-7.88), presence of retinal break greater than 1 clock-hour (p < 0.05, OR 3.41, 1.06-11.02), and presence of grade C or D proliferative vitreoretinopathy (PVR) (p < 0.01, OR 31.83, 95% CI, 3.59-282.24), gained statistical significance. Conclusions: Only pseudophakia, a large retinal break, and/or PVR was associated with an increased likelihood of failure. © 2013 Canadian Ophthalmological Society. All rights reserved.Link_to_subscribed_fulltex

The Mortality and Overall Survival Trends of Primary Liver Cancer in the United States

BackgroundRecent trends of hepatocellular carcinoma (HCC) mortality and outcome remain unknown in the United States. We investigated the recent trends of primary liver cancer (excluding intrahepatic cholangiocarcinoma) mortality and HCC stage, treatment, and overall survival (OS) in the United States.MethodsThe National Center for Health Statistics Database was analyzed to investigate the trend of primary liver cancer mortality. We analyzed the Surveillance, Epidemiology, and End Results 18 Database to assess the temporal trend of tumor size, stage, treatment, and OS of HCC. We investigated the association between HCC diagnosis year and OS using Cox regression analysis. All statistical tests were 2-sided.ResultsDuring 2000-2018, liver cancer mortality rates increased until 2013, plateaued during 2013-2016 (annual percent change = 0.1%/y, 95% confidence interval [CI] = -2.1%/y to 2.4%/y, P = .92), and started to decline during 2016-2018 (annual percent change = -1.5%/y, 95% CI = -3.2%/y to 0.2%/y, P = .08). However, mortality continues to increase in American Indian and Alaska Native, individuals aged 65 years or older, and in 33 states. There was a 0.61% (95% CI = 0.53% to 0.69%, P &lt; .001) increase in localized stage HCC and a 0.86-mm (95% CI = -1.10 to -0.62 mm, P &lt; .001) decrease in median tumor size per year. The 1-year OS rate increased from 36.3% (95% CI = 34.3% to 38.3%) to 58.1% (95% CI = 56.9% to 59.4%) during 2000-2015, and the 5-year OS rate almost doubled from 11.7% (95% CI = 10.4% to 13.1%) to 21.3% (95% CI = 20.2% to 22.4%) during 2000-2011. Diagnosis year (per year) (adjusted hazard ratio = 0.96, 95% CI = 0.96 to 0.97) was independently associated with OS in multivariable analysis.ConclusionsPrimary liver cancer mortality rates have started to decline in the United States with demographic and state-level variation. With an increasing detection of localized HCC, the OS of HCC has improved over the past decades

Comparison of Surgical Resection and Systemic Treatment for Hepatocellular Carcinoma with Vascular Invasion: National Cancer Database Analysis

IntroductionSmall studies from outside of the USA suggest excellent outcomes after surgical resection for hepatocellular carcinoma (HCC) with vascular invasion. The study aims to (1) compare overall survival after surgical resection and systemic therapy among patients with HCC and vascular invasion and (2) determine factors associated with receipt of surgical resection in a US population.MethodsHCC patients with AJCC clinical TNM stage 7th T3BN0M0 diagnosed between 2010 and 2017 from the National Cancer Database were analyzed. Cox and logistic regression analyses identified factors associated with overall survival and receipt of surgical resection.ResultsOf 11,259 patients with T3BN0M0 HCC, 325 (2.9%) and 4,268 (37.9%) received surgical resection and systemic therapy, respectively. In multivariable analysis, surgical resection was associated with improved survival compared to systemic therapy (adjusted hazard ratio: 0.496, 95% confidence interval: 0.426-0.578) with a median survival of 21.4 and 8.1 months, respectively. Superiority of surgical resection was observed in noncirrhotic and cirrhotic subgroups and propensity score matching and inverse probability of treatment weighting adjusted analysis. Asians were more likely to receive surgical resection, whereas Charlson comorbidity ≥3, elevated alpha-fetoprotein, smaller tumor size, care in a community cancer program, and the South or West region were associated with a lower likelihood of surgical resection.ConclusionHCC patients with vascular invasion may benefit from surgical resection compared to systemic therapies. Demographic and clinical features of HCC patients and region and type of treating facility were associated with surgical resection versus systemic treatment